Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog

Abstract

Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance ( < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance ( < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.

The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy

“…Our data suggest that the beneficial effect of KBP-088 and other DACRAs on fasting blood glucose and HbA1c levels (Feigh et al, 2014;Hjuler et al, 2017) is mediated though activation of both the CTR and the AMY-R, an effect not driven by body weight loss, and thereby appears to be independent of reductions in adipocyte size and numbers, which are known to be essential for the weight-lowering effects of both DACRAs and amylin (Gydesen et al, 2017;Hjuler et al, 2017;Duffy et al, 2018). With respect to the post-prandial effects on blood glucose, one could speculate that the effect of amylin on this parameter is mainly driven by its ability to lower blood glucose by suppressing inappropriate glucagon secretion and slowing gastric emptying as well as its anorectic effect (Hay et al, 2015;Hay, 2017).…”

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

“…The receptor pharmacology analysis of these peptides has relied on purchased stably transfected cell lines, which are not especially well characterized. It is not clear how much activity of the ligands occurs via free CTR in this transfected cell system (Andreassen et al, ; Gydesen et al, ; ,b). As noted above, to determine affinity at a CTR/RAMP complex, displacement of [ 125 I]‐amylin (or 125 I‐CGRP for the AMY 1 receptor) is the most reliable measure of true AMY receptor affinity.…”

“…Recently, a number of CT mimetics, known by ‘KBP’ codes, for example, KBP‐042, KBP‐088 and KBP‐089, have been described (Patent WO 2015/071229). These molecules are reported to maintain the high efficacy of salmon CT, whilst improving tolerability in rats (Gydesen et al, ). A similar strategy appears to have been employed for the development of davalintide, which appears to be more effective at reducing body weight and food intake compared to amylin in rats (Mack et al, ).…”

“…Interestingly, the KBP compounds maintain the long‐acting ability of salmon CT to stimulate signalling in cell culture models (Andreassen et al, ; Gydesen et al, ). The receptor pharmacology of the KBP peptides has not been extensively studied, and so far, the peptides have only been tested at CTR, AMY 3 and CGRP receptors (Andreassen et al, ; Gydesen et al, ; ). They have been shown to activate both CT and AMY 3 receptors but not CGRP receptors, similar to salmon CT, and are known as ‘DACRAs’ – dual amylin and CT receptor agonists; salmon CT is a natural DACRA.…”

Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss

“…Potent dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity (Gydesen et al, 2016;Hjuler et al, 2016;Gydesen et al, 2017b;Hjuler et al, 2017). DACRAs activate not only the amylin receptor, but also the calcitonin receptor (Andreassen et al, 2014a).…”